Project 3: Progesterone and Neurogenic Plasticity in Aging and AD. In this Program Project, we jointly hypothesize that the sex steroid hormone progesterone (P4) promotes the brain's molecular, synaptic, cellular, and behavioral plasticity and reduces its vulnerability to the development of Alzheimer's disease (AD). We further hypothesize that the reproductive endocrine status, duration of ovariprivation and presence of AD related pathology regulates the plasticity response to ovarian steroids. The potential neural benefits of hormone therapy is constrained, at least in part, by our currently limited knowledge of the (1) basic neurobiology of P4, (2) the neural response to clinically relevant progestogens, (3) the complex modulatory interactions between progesterone and estrogen and (4) the impact of extended ovarian hormone privation and AD neuropathology on the brain's responsiveness to progesterone and estrogen. The objectives of Project 3 are to determine 1) the neurogenic potential of progestogens;2) their associated mechanism of neurogenic action;3) the impact of age and endocrine status on ovarian hormone- induced neurogenesis;and 4) the impact of Alzheimer's disease pathology progression on gonadal hormone regulated neurogenesis. To achieve these objectives, we have developed an interactive research plan that capitalizes on the expertise throughout the program project. Consistent with the Specific Aim structure of all projects within the Program, Specific Aim 1 will determine the direct effect of P4 on neurogenesis and mechanisms of action. Specific Aim 2 will determine the proliferative efficacy of clinically relevant progestins. Specific Aim 3 will determine P4 regulation of 17 beta-estradiol (E2)-induced neurogenesis. Specific Aim 4 will determine the impact of E2/P4 on neurogenesis in rat models of human perimenopause and menopause. Specific Aim 5 will determine the impact of E2/P4 on neurogenesis in the SxTgAD mouse model of AD. To conduct these investigations, 5 technological approaches will be extensively utilized: in vitro culture of rat and mouse neural progenitors derived from adult dentate gyrus, fluorescent immunocytochemistry, biochemical analyses of kinase activation and protein expression, gene arrays for cell cycle gene expression and in vivo BrdU labeling followed by unbiased stereology. Because the proposed studies were designed to address issues of clinical relevance, results of these analyses should contribute to our (1) basic science understanding of progesterone regulation of cellular neurogenic plasticity in the hippocampus and the factors that control this 'response and (2) understanding the basis of disparities across clinical studies of hormone therapy and basic science analyses of E2/P4 in brain.